Apolipoprotein E and Gray Matter Loss in Mild Cognitive Impairment and Alzheimer’s Disease Spampinato MV, Goldsberry G, Mintzer J, Rumboldt Z Medical University of South Carolina Charleston, SC

BACKGROUND ApoE (chromosome 19) - involved in cell metabolism, repairing neuronal injury and the aging process Apolipoprotein E ε4 allele (apoE4) -known genetic risk factor for AD with a dose-dependent effect on age of onset -linked to amyloid β peptide accumulation, synaptic dysfunction, and neuronal loss resulting in neurodegeneration Mahley RW et al. PNAS 2006;103:

PURPOSE To retrospectively examine the influence of apoE4 on the rate of gray matter (GM) volume loss over 24-months 1.with conversion from MCI to AD 2.with stable amnestic MCI Voxel-based morphometry analysis: comparison of whole-brain GM volume between groups Hypothesis: Greater hippocampal and neocortical volume loss in apoE4 carriers

ADNI cohort = 818 subjects 396 MCI 193 AD 229 normal controls METHODS

ADNI cohort = 818 subjects 396 MCI 125 clinical conversion to AD 271 stable MCI METHODS

AD Documented conversion from MCI to AD Known apoE genotype Longitudinal MRI data MCI Clinical follow-up showing stable cognitive status over 3 years Known apoE genotype Longitudinal MRI data METHODS Inclusion Criteria

METHODS MRI AD 1.Baseline MRI: 12 months before MCI-AD conversion 2.Second MRI: MCI-AD conversion 3.Third MRI: 12 months after conversion MCI 1.Baseline MRI: baseline visit 2.Second MRI: 12-month visit 3.Third MRI: 24-month visit

Clinical evaluation: baseline,12-month, and 24-month follow-up Clinical Dementia Rating (CDR) Clinical Dementia Rating Sum of Boxes (CDR-SB) Determination of apoE genotype - DNA from peripheral blood samples (ADNI Biomarker Core Laboratory) METHODS

POST-PROCESSING MR DATA Normalized Modulated Segmented Normalized Modulated Segmented Smoothed Raw MPRAGE Image SPM5 WITH VBM5 TOOLBOX

Statistical Analysis Clinical data Comparison MCI ε4 carriers vs. non carriers AD ε4 carriers vs. non carriers Pearson χ2 (gender, CDR) One-way Anova (age, education, CDR-SB)

Statistical Analysis Longitudinal comparison of imaging data in SPM Paired t-test with family-wise error correction for multiple comparisons (p-value of 0.05) GM volume baseline vs. 12 months follow-up GM volume 12 months vs. 24 months follow-up

Results

RESULTS Stable MCI ApoE4 carriers Baseline vs. 12 month MRI (N=24) No significant differences in GM vol. in the 2nd year Longitudinal analysis GM volume

(N=24) No significant difference in GM volume during 2 years RESULTS MCI ApoE4 non-carriers

RESULTS AD ApoE 4 carriers 12 months before the diagnosis of AD (N=27) Longitudinal analysis GM volume

RESULTS AD ApoE4 carriers 12 months after conversion (N=27) Longitudinal analysis GM volume

RESULTS AD ApoE4 non-carriers (N=20) No significant difference in GM volume during 2 years

RESULTS ApoE 4 carriers 12 months post MCI AD conversion Stable MCI 12 month follow-up 12 months before MCI AD conversion

BRAAK STAGES Distribution of AD neuropathologic changes (+++ neurofibrillary tangles) Stages I-II, clinically silent: perirhinal region Stages III-IV, incipient AD: limbic system Stages V-VI, advanced AD: neocortex Braak H, Braak E. J Neural Transm Suppl 1998 Nagy Z et al. Dement Geriatr Cogn Disord 1999

Imaging Data Significant GM volume loss in apoE4 carriers in patients with AD and stable MCI Perirhinal cortex (MCI) Insula (MCI and AD) Hippocampi (AD) Neocortex (AD > MCI) No significant GM volume loss in non apoE4 carriers with AD and MCI

CONCLUSION The apoE4 carrier status is associated with atrophy of the hippocampi and neocortex in MCI-AD conversion In apoE4 non-carriers with MCI-AD conversion there is a dissociation between worsening cognitive status and progression of GM atrophy

CONCLUSION 1.Understanding the role of apoE genotype in the progression of cognitive decline and neurodegeneration is important to optimize treatment regimens 2.ApoE genotype testing is an important element of clinical trials targeting patients with probable Alzheimer’s disease